dbSNP rs2124280504: HPRT1:p.Met1? (chrX-134460312-A-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000194.3(HPRT1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

HPRT1
NM_000194.3 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.38

Variant links:

Genes affected

HPRT1 (HGNC:5157): (hypoxanthine phosphoribosyltransferase 1) The protein encoded by this gene is a transferase, which catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate. This enzyme plays a central role in the generation of purine nucleotides through the purine salvage pathway. Mutations in this gene result in Lesch-Nyhan syndrome or gout.[provided by RefSeq, Jun 2009]

HPRT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 43 codons. Genomic position: 134473458. Lost 0.193 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-134460312-A-G is Pathogenic according to our data. Variant chrX-134460312-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1700018.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	ENST00000298556.8	NP_000185.1	P00492A0A140VJL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	1	NM_000194.3	ENSP00000298556.7		P00492
HPRT1	ENST00000462974.5 link	n.-39A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1016860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

328414

African (AFR)

AF:

0.00

AC:

AN:

22320

American (AMR)

AF:

0.00

AC:

AN:

27478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17504

East Asian (EAS)

AF:

0.00

AC:

AN:

24347

South Asian (SAS)

AF:

0.00

AC:

AN:

48438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25463

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3063

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

805793

Other (OTH)

AF:

0.00

AC:

AN:

42454

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lesch-Nyhan syndrome

Pathogenic:1

Jul 14, 2022

Institute of Human Genetics, Cologne University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.64

BayesDel_noAF

Pathogenic

0.68

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.46

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

PhyloP100

3.4

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.61

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.054

Polyphen

0.070

Vest4

0.90

MutPred

0.99

Loss of sheet (P = 0.1907);

MVP

1.0

ClinPred

0.95

GERP RS

3.1

PromoterAI

-0.58

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.89

Mutation Taster

=6/194

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over